As an extension of our work with anxious and depressed patients, we have sought to develop pharmacologic models of anxiety in non-human primates. The benzodiazepine receptor active antagonist, Beta-carboline-3-carboxylic acid-ethyl ester (Beta-CCE) induced dose related increases in behavioral activation, plasma cortisol, and heart rate in rhesus monkeys. All of these effects were blocked by clinically relevant doses of diazepam but only selective parts of the Beta-CCE induced syndrome were blocked by clonidine or propranolol. The recently sequenced peptide corticotropin releasing factor (CRF) when given intraventricularly also was associated with an increase in plasma cortisol, but did not lead to an increase in behavioral activation. With CRF administration, increases in plasma catecholamines were evident only at very high doses. In an attempt to localize neural sites for CRF and possibly Beta-CCE actions, an in vitro light microscopic autoradiographic method for labeling specific CRF receptors in brain was developed. These receptors which are most densely localized in Lamina IV of the neocortex, the median eminence of the hypothalamus, and the amygdala, suggest a circuit of brain structures which may be involved in certain aspects of anxiety.